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Frontiers in Immunology 2024Sepsis remains a major source of morbidity and mortality in neonates, and characterization of immune regulation in the neonatal septic response remains limited. HVEM is...
INTRODUCTION
Sepsis remains a major source of morbidity and mortality in neonates, and characterization of immune regulation in the neonatal septic response remains limited. HVEM is a checkpoint regulator which can both stimulate or inhibit immune responses and demonstrates altered expression after sepsis. We hypothesized that signaling via HVEM would be essential for the neonatal response to sepsis, and that therefore blockade of this pathway would improve survival to septic challenge.
METHODS
To explore this, neonatal mice were treated with cecal slurry (CS), CS with Anti-HVEM antibody (CS-Ab) or CS with isotype (CS-IT) and followed for 7-day survival. Mice from all treatment groups had thymus, lung, kidney and peritoneal fluid harvested, weighed, and stained for histologic evaluation, and changes in cardiac function were assessed with echocardiography.
RESULTS
Mortality was significantly higher for CS-Ab mice (72.2%) than for CS-IT mice (22.2%). CS resulted in dysregulated alveolar remodeling, but CS-Ab lungs demonstrated significantly less dysfunctional alveolar remodeling than CS alone (MCL 121.0 CS vs. 87.6 CS-Ab), as well as increased renal tubular vacuolization. No morphologic differences in alveolar septation or thymic karyorrhexis were found between CS-Ab and CS-IT. CS-Ab pups exhibited a marked decrease in heart rate (390.3 Sh vs. 342.1 CS-Ab), stroke volume (13.08 CS-IT vs. 8.83 CS-Ab) and ultimately cardiac output (4.90 Sh vs. 3.02 CS-Ab) as well as a significant increase in ejection fraction (73.74 Sh vs. 83.75 CS-Ab) and cardiac strain (40.74 Sh vs. 51.16 CS-Ab) as compared to CS-IT or Sham animals.
DISCUSSION
While receptor ligation of aspects of HVEM signaling, via antibody blockade, appears to mitigate aspects of lung injury and thymic involution, stimulatory signaling via HVEM still seems to be necessary for vascular and hemodynamic resilience and overall neonatal mouse survival in response to this experimental polymicrobial septic insult. This dissonance in the activity of anti-HVEM neutralizing antibody in neonatal animals speaks to the differences in how septic cardiac dysfunction should be considered and approached in the neonatal population.
Topics: Animals; Mice; Animals, Newborn; Signal Transduction; Neonatal Sepsis; Receptors, Tumor Necrosis Factor, Member 14; Disease Models, Animal; Female; Heart Diseases; Lung; Sepsis
PubMed: 38774873
DOI: 10.3389/fimmu.2024.1365174 -
Clinical and Experimental Hepatology Dec 2023Methotrexate (MTX) causes oxidative stress-related liver damage. Our objective was to investigate the protective effects of vitamin E against MTX-induced hepatotoxicity...
AIM OF THE STUDY
Methotrexate (MTX) causes oxidative stress-related liver damage. Our objective was to investigate the protective effects of vitamin E against MTX-induced hepatotoxicity through histopathological methods and flow cytometry.
MATERIAL AND METHODS
The rats were assigned to four groups: Control (2 ml saline for 5 days), MTX (20 mg/kg intraperitoneally (i.p.) only on the initial day of the study), MTX + vitamin E (20 mg/kg MTX (i.p.) only on the first day, and 100 mg/kg vitamin E (i.p.) was applied for 5 days during the study), Vitamin E (100 mg/kg of vitamin E (i.p.) was given for five days). Histopathologic changes and the flow cytometric apoptotic index were evaluated for liver tissue. The Kruskal-Wallis test was used for comparisons between groups. The statistical significance level was accepted as < 0.05.
RESULTS
In the histopathological analysis, hepatocyte degeneration, dilatation of sinusoids, mononuclear cell infiltration, hydropic degeneration in hepatocytes, vacuolization, and pycnotic nucleus were observed in the MTX group. In the MTX + vitamin E group, hepatocyte degeneration, pycnotic nuclei, and dilatation in sinusoids were significantly lower compared to the MTX group. In the MTX group, glycogen accumulation in hepatocytes was lower compared to the control group. In the MTX + vitamin E group, glycogen accumulation in hepatocy-tes was higher compared to the MTX group. The flowcytometric apoptotic index (AI) percentage in the MTX group was 34.4% and in the MTX + vitamin E group the value was 9.4%.
CONCLUSIONS
Our results demonstrated that vitamin E ameliorates MTX-induced liver damage. Co-using vitamin E and MTX drugs will be beneficial for the treatment of various diseases.
PubMed: 38774203
DOI: 10.5114/ceh.2023.132251 -
Ecotoxicology and Environmental Safety Jul 2024Microcystins (MCs) are toxic to the central nervous system of mammals. However, the direct toxicity of MCs on mammalian brain cells and the involved molecular mechanisms...
Microcystins (MCs) are toxic to the central nervous system of mammals. However, the direct toxicity of MCs on mammalian brain cells and the involved molecular mechanisms are not fully elucidated. Here, we incubated primary astrocytes, the major glial cell-type in the brain, with 0-12.5 μM concentrations of MC-LR for 48 h, and the impairment was evaluated. We found that MC-LR caused significant increases in the cell viability at the range of 0.05-1 μM concentrations with the highest density at 0.1 μM concentration. Treatment with 0.1 μM MC-LR induced YAP nuclear translocation and decreased the ratio of p-YAP to YAP. It also decreased mRNA levels of the upstream regulator (AMOT), and enhanced expressions of YAP interacted genes (Egfr, Tead1, and Ctgf) in primary astrocytes. Overexpression of AMOT significantly attenuated the increase of MC-LR-induced astrocyte proliferation and the expression of YAP downstream genes. These results indicate that Hippo signaling contributed to MC-LR-caused astrocyte proliferation. Further, reactive astrogliosis was observed in the mice brain after MC-LR exposure to environmentally relevant concentrations (20 or 100 μg/L) through drinking water for 16 weeks. Pathological observations revealed that 100 μg/L MC-LR exposure caused neuronal damages with characteristics of shrunken or vacuolation in the region of the cerebral cortex, striatum and cerebellum. These results were accompanied with increased oxidative stress and inflammatory response. Our data reveal the potential astrocytic mechanisms in MC-induced neurotoxicity and raise an alarm for neurodegenerative disease risk following daily exposure to MC-LR.
Topics: Microcystins; Animals; Astrocytes; Marine Toxins; Hippo Signaling Pathway; Signal Transduction; Cell Proliferation; Mice; Protein Serine-Threonine Kinases; YAP-Signaling Proteins; Cell Survival; Transcription Factors; ErbB Receptors; TEA Domain Transcription Factors; DNA-Binding Proteins
PubMed: 38772146
DOI: 10.1016/j.ecoenv.2024.116480 -
ELife May 2024Rab GTPases are representative targets of manipulation by intracellular bacterial pathogens for hijacking membrane trafficking. recruits many Rab GTPases to its vacuole...
Rab GTPases are representative targets of manipulation by intracellular bacterial pathogens for hijacking membrane trafficking. recruits many Rab GTPases to its vacuole and exploits their activities. Here, we found that infection-associated regulation of Rab10 dynamics involves ubiquitin signaling cascades mediated by the SidE and SidC families of ubiquitin ligases. Phosphoribosyl-ubiquitination of Rab10 catalyzed by the SidE ligases is crucial for its recruitment to the bacterial vacuole. SdcB, the previously uncharacterized SidC-family effector, resides on the vacuole and contributes to retention of Rab10 at the late stages of infection. We further identified MavC as a negative regulator of SdcB. By the transglutaminase activity, MavC crosslinks ubiquitin to SdcB and suppresses its function, resulting in elimination of Rab10 from the vacuole. These results demonstrate that the orchestrated actions of many effectors fine-tune the dynamics of Rab10 during infection.
Topics: rab GTP-Binding Proteins; Legionella pneumophila; Bacterial Proteins; Humans; Vacuoles; Host-Pathogen Interactions; Ubiquitination; Animals; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 38771316
DOI: 10.7554/eLife.89002 -
Veterinary Research Forum : An... 2024a repulsive obligate blood feeder, is a three-host tick inflicting tremendous damage. Blood-sucking initiates tick-pathogen-host interactions along with alterations in...
a repulsive obligate blood feeder, is a three-host tick inflicting tremendous damage. Blood-sucking initiates tick-pathogen-host interactions along with alterations in the expression levels of numerous bioactive ingredients. Key molecules regulating blood meals were identified using the transcriptomic approach. A total number of 744 transcripts showed statistically significantly differential expression including 309 significantly upregulated transcripts and 435 significantly downregulated transcripts in semiengorged female ticks compared to unfed ticks, all collected in 2021. The top 10 differentially upregulated transcripts with explicit functional annotations included turripeptide OL55-like protein, valine tRNA ligase-like protein and ice-structuring glycoprotein-like protein. The top 10 differentially down-regulated transcripts were uncharacterized proteins. Gene Ontology (GO) enrichment analysis revealed four associated terms in the cellular component category and 16 in the molecular function category among the top 20 terms. Differentially expressed genes (DEGs) were enriched in GO terms ID 0000323 (lytic vacuole) and ID 0005773 (vacuole). The top 20 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways included metabolism, cellular processes, organismal systems and human diseases. The DEGs were enriched in the KEGG term ID: ko-04142 (lysosome pathway) associated with intracellular digestion in the tick midgut epithelium. Molecular markers annotated via comparative transcriptomic profiling were expected to be candidate markers for the purpose of tick control.
PubMed: 38770198
DOI: 10.30466/vrf.2024.2011271.4007 -
BMC Nephrology May 2024Lipoprotein glomerulopathy (LPG) is a apolipoprotein E (ApoE)-related glomerular disease and has been associated with type III hyperlipidemia. Without appropriate...
BACKGROUND
Lipoprotein glomerulopathy (LPG) is a apolipoprotein E (ApoE)-related glomerular disease and has been associated with type III hyperlipidemia. Without appropriate treatment, chronic kidney disease (CKD) caused by LPG progresses, and approximately half of the patients develop end-stage kidney disease within 1-27 years of disease onset. However, few studies have highlighted the clinical course of cardiovascular diseases (CVDs) in patients with LPG. Herein, we report the first case of LPG in which the CVD risk was assessed using arterial stiffness.
CASE PRESENTATION
A 32-year-old Japanese man was referred to our hospital due to persistent proteinuria. Kidney biopsy showed markedly dilated capillary lumens containing pale-stained thrombi, which stained positively with Oil Red O. Electron microscopy revealed the presence of thrombi in the capillary lumen with low electron density and vacuoles of various sizes in part of the thrombi. Toluidine blue and Sudan IV stains were used to stain the thin sections of Epon-embedded tissue samples for electron microscopy. Sudan IV-positive droplets were observed in the capillary lumens, vascular walls, and cytoplasm of tubular cells. Increased serum ApoE concentration was observed. Liquid chromatography-tandem mass spectrometry of laser-microdissected glomeruli from paraffin sections revealed an increase in ApoE. Direct deoxyribonucleic acid sequencing of ApoE revealed a heterozygous ApoE Sendai mutation (Arg145Pro). The patient was finally diagnosed with LPG with heterozygosity for ApoE-Sendai mutation (Arg145Pro). Notably, at the time of diagnosis, he had markedly increased arterial stiffness for his age. Arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV), which was equivalent to that of a 56-year-old man. After three months of treatment with fenofibrate and losartan, a significant reduction in proteinuria was achieved along with an improvement in baPWV. Furthermore, these effects were maintained despite the lack of decrease in serum ApoE levels.
CONCLUSION
Herein, we report the case of a patient with LPG with markedly increased arterial stiffness at the time of diagnosis, in whom combination therapy with fenofibrate and losartan successfully improved proteinuria and arterial stiffness. To the best of our knowledge, this is the first case report of LPG in which CVD risk was assessed using arterial stiffness.
Topics: Humans; Male; Adult; Losartan; Vascular Stiffness; Fenofibrate; Drug Therapy, Combination; Hypolipidemic Agents; Kidney Diseases; Apolipoproteins E
PubMed: 38769490
DOI: 10.1186/s12882-024-03612-z -
Nature Communications May 2024The identification of genes involved in salinity tolerance has primarily focused on model plants and crops. However, plants naturally adapted to highly saline...
The identification of genes involved in salinity tolerance has primarily focused on model plants and crops. However, plants naturally adapted to highly saline environments offer valuable insights into tolerance to extreme salinity. Salicornia plants grow in coastal salt marshes, stimulated by NaCl. To understand this tolerance, we generated genome sequences of two Salicornia species and analyzed the transcriptomic and proteomic responses of Salicornia bigelovii to NaCl. Subcellular membrane proteomes reveal that SbiSOS1, a homolog of the well-known SALT-OVERLY-SENSITIVE 1 (SOS1) protein, appears to localize to the tonoplast, consistent with subcellular localization assays in tobacco. This neo-localized protein can pump Na into the vacuole, preventing toxicity in the cytosol. We further identify 11 proteins of interest, of which SbiSALTY, substantially improves yeast growth on saline media. Structural characterization using NMR identified it as an intrinsically disordered protein, localizing to the endoplasmic reticulum in planta, where it can interact with ribosomes and RNA, stabilizing or protecting them during salt stress.
Topics: Chenopodiaceae; Plant Proteins; Salt Tolerance; Gene Expression Regulation, Plant; Vacuoles; Salinity; Sodium Chloride; Endoplasmic Reticulum; Salt Stress; Proteomics; Nicotiana; Transcriptome
PubMed: 38769297
DOI: 10.1038/s41467-024-48595-5 -
Indian Journal of Ophthalmology May 2024To investigate the histopathological findings of the anterior lens capsule in pediatric patients who had surgery for cataracts.
PURPOSE
To investigate the histopathological findings of the anterior lens capsule in pediatric patients who had surgery for cataracts.
METHODS
This study is a prospective interventional study. Anterior capsule tissue samples that were obtained by the anterior capsulotomy method during phacoemulsification surgery were fixed and examined under a transmission electron microscope.
RESULTS
Twenty-two eyes of 19 patients who were diagnosed with congenital and juvenile cataracts were included in this study. Five patients had associated systemic diseases, including hydrocephalus, cerebral palsy, prematurity, juvenile myelomonocytic leukemia, and Down's syndrome. Electron microscopic evaluation demonstrated single-layered epithelium under the capsule, degenerated organelles with round-oval and prismatic-oval nuclei, and degenerated mitochondria and heterochromatin-rich nuclei. In the case with cerebral palsy, collagen fibrils of the connective tissue and fibroblast-like cells were observed replacing the epithelium that should be underneath the capsule in both eyes, and there was a disorganized distribution of collagen fibrils and vacuole structures in the cytoplasm of fibroblast-like cells.
CONCLUSION
Similar histopathological findings were found in pediatric cataracts with or without systemic disease except in one cerebral palsy case. The absence of lens epithelium may have been a result of degeneration in this patient, and this can be attributed to the presence of systemic inflammation and gliosis in cerebral palsy. The absence of lens epithelium can play a role in the development of dense subcapsular fibrosis and cataract formation.
PubMed: 38767535
DOI: 10.4103/IJO.IJO_2957_23 -
PeerJ 2024Genetic variation for salt tolerance remains elusive in jamun ().
BACKGROUND
Genetic variation for salt tolerance remains elusive in jamun ().
METHODS
Effects of gradually increased salinity (2.0-12.0 dS/m) were examined in 20 monoembryonic and 28 polyembryonic genotypes of jamun. Six genotypes were additionally assessed for understanding salt-induced changes in gas exchange attributes and antioxidant enzymes.
RESULTS
Salt-induced reductions in leaf, stem, root and plant dry mass (PDM) were relatively greater in mono- than in poly-embryonic types. Reductions in PDM relative to control implied more adverse impacts of salinity on genotypes CSJ-28, CSJ-31, CSJ-43 and CSJ-47 (mono) and CSJ-1, CSJ-24, CSJ-26 and CSJ-27 (poly). Comparably, some mono- (CSJ-5, CSJ-18) and poly-embryonic (CSJ-7, CSJ-8, CSJ-14, CSJ-19) genotypes exhibited least reductions in PDM following salt treatment. Most polyembryonic genotypes showed lower reductions in root than in shoot mass, indicating that they may be more adept at absorbing water and nutrients when exposed to salt. The majority of genotypes did not exhibit leaf tip burn and marginal scorch despite significant increases in Na and Cl, suggesting that tissue tolerance existed for storing excess Na and Cl in vacuoles. Jamun genotypes were likely more efficient in Cl exclusion because leaf, stem and root Cl levels were consistently lower than those of Na under salt treatment. Leaf K was particularly little affected in genotypes with high leaf Na. Lack of discernible differences in leaf, stem and root Ca and Mg contents between control and salt treatments was likely due to their preferential uptake. Correlation analysis suggested that Na probably had a greater inhibitory effect on biomass in both mono- and poly-embryonic types. Discriminant analysis revealed that while stem and root Cl probably accounted for shared responses, root Na, leaf K and leaf Cl explained divergent responses to salt stress of mono- and poly-embryonic types. Genotypes CSJ-18 and CSJ-19 seemed efficient in fending off oxidative damage caused by salt because of their stronger antioxidant defences.
CONCLUSIONS
Polyembryonic genotypes CSJ-7, CSJ-8, CSJ-14 and CSJ-19, which showed least reductions in biomass even after prolonged exposure to salinity stress, may be used as salt-tolerant rootstocks. The biochemical and molecular underpinnings of tissue tolerance to excess Na and Cl as well as preferential uptake of K, Ca, and Mg need to be elucidated.
Topics: Syzygium; Genotype; Salt Stress; Salt Tolerance; Plant Leaves; Plant Roots; Salinity; Antioxidants
PubMed: 38766484
DOI: 10.7717/peerj.17311 -
BioRxiv : the Preprint Server For... May 2024Upon entry into host cells, the facultative intracellular bacterium ( .) uses its type IV secretion system, Dot/Icm, to secrete ~330 bacterial effector proteins into...
Upon entry into host cells, the facultative intracellular bacterium ( .) uses its type IV secretion system, Dot/Icm, to secrete ~330 bacterial effector proteins into the host cell. Some of these effectors hijack endoplasmic reticulum (ER)-derived vesicles to form the -containing vacuole (LCV). Despite extensive investigation over decades, the fundamental question persists: Is the LCV membrane distinct from or contiguous with the host ER network? Here, we employ advanced photobleaching techniques, revealing a temporal acquisition of both smooth and rough ER (sER and rER) markers on the LCV. In the early stages of infection, the sER intimately associates with the LCV. Remarkably, as the infection progresses, the LCV evolves into a distinct niche comprising an rER membrane that is independent of the host ER network. We discover that the effector LidA binds to and recruits two host proteins of the Rab superfamily, Rab10, and Rab4, that play significant roles in acquiring sER and rER membranes, respectively. Additionally, we identify the pivotal role of a host ER-resident protein, BAP31, in orchestrating the transition from sER to rER. While previously recognized for shuttling between sER and rER, we demonstrate BAP31's role as a Rab effector, mediating communication between these ER sub-compartments. Furthermore, using genomic deletion strains, we uncover a novel effector, Lpg1152, essential for recruiting BAP31 to the LCV and facilitating its transition from sER to rER. Depletion of BAP31 or infection with an isogenic strain lacking Lpg1152 results in a growth defect. Collectively, our findings illuminate the intricate interplay between molecular players from both host and pathogen, elucidating how orchestrates the transformation of its residing vacuole membrane from a host-associated sER to a distinct rER membrane that is not contiguous with the host ER network.
PubMed: 38765994
DOI: 10.1101/2024.05.10.593622